Objectives of the project are as follows: first to identify sexual dimorphisms and the role of gonadal steroids in the regulation of neural and glial signal transduction, proliferation, and survival; second, to develop an animal model for behavioral effects of gonadal steroid withdrawal and for the differential behavioral effects of acute alterations in gonadal steroid levels. These objectives serve two overall goals: 1) Understanding neuroregulatory mechanisms of gonadal steroids of relevance for affective disorders; and 2) Defining the substrate of differential sensitivity, the process by which the same hormonal stimulus can elicit different responses in different subjects. Findings in the past year include the following: 1) Dramatic upregulation of cortical stimulated EPSPs in rat amygdalar neurons by estradiol and the ER alpha agonist PPT, with an almost three fold greater enhancement in females compared with males; 2) Demonstration of greater concentration of ER alpha in female compared with male amygdala; 3) Demonstration of subacute, repeated stress-induced downregulation of both ER alpha and phosphotyrosine kinase in the amygdala; 4) Confirmation and extension of earlier findings that estradiol and the ER alpha agonist PPT have greater stimulatory effects on ERK in cortical neurons from female rats than males; 5) Demonstration of strain differences in the effects of estradiol on behavior in an animal model of depression, the forced swim test: Wistar rats show no antidepressant effect of estradiol but do show estradiol withdrawal-induced immobilization, while Long Evans rats show an antidepressant effect of estradiol but no effects of estradiol withdrawal. These data suggest that gender and gonadal steroids regulate neuronal excitability in brain regions mediating the stress response and implicated in depression. The strain-related differences in behavioral response to estradiol are very promising as a means for identifying possible genomic underpinnings of differential sensitivity to gonadal steroid precipitated mood disturbances.